tbuckley/cabot-search huggingface dataset:
The von Willebrand factor–binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A
Authors: Cihan Ay, Katarina D. Kovacevic, Daniel Kraemmer, Christian Schoergenhofer, Georg Gelbenegger, Christa Firbas, Peter Quehenberger, Petra Jilma-Stohlawetz, James C. Gilbert, Shuhao Zhu, Martin Beliveau, Franz Koenig, Alfonso Iorio, Bernd Jilma, Ulla Derhaschnig, Ingrid Pabinger
Journal: Blood (2022)

Factor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.
Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy
Authors: Quanwei Sun, Jinming Yang, Wei Shen, Huiyu Lu, Xiaohui Hou, Yang Liu, Yujing Xu, Qinghua Wu, Zihua Xuan, Ye Yang, Dengke Yin
Journal: Biomaterials (2022)
Space Is the Place: Mapping the Cell–Cell Interactions That Predict Immunotherapy Responses in Melanoma
Authors: Inna Smalley, Keiran S.M. Smalley
Journal: Cancer Research (2022)

Abstract Although immune checkpoint inhibition (ICI) has revolutionized the treatment of advanced melanoma, reliable predictive biomarkers are still lacking. In this issue of Cancer Research, Antoranz and colleagues used RNA sequencing and multiplexed IHC to study the spatial immune landscape of pretreatment melanoma specimens from patients who either responded or did not respond to antiprogrammed death protein 1 (PD-1) therapy. The authors identified the spatial interaction between cytotoxic T cells and M1-like macrophages expressing PD-L1 at the tumor boundary as predictive of responses to immune checkpoint inhibition. These studies pave the way for the development of new spatial biomarkers to identify patients most likely to benefit from ICI therapy. See related article by Antoranz et al., p. 3275
Bronchial Remodeling-based Latent Class Analysis Predicts Exacerbations in Severe Preschool Wheezers
Authors: Michael Fayon, Fabien Beaufils, Pauline Esteves, Maryline Campagnac, Elise Maurat, Marine Michelet, Valerie Siao-Him-Fa, Frederic Lavrand, Guillaume Simon, Hugues Begueret, Patrick Berger, Françoise Auriol, Sylvain Blanchon, Dominique Carles, Vincent Boisserie-Lacroix, François Brémont, Stéphanie Bui, Marie-Luce Choukroun, Stéphane Debelleix, Hala Feghali, Géraldine Labouret, Audrey Martin Blondel, Sébastien Marais, Marie Mittaine, Fabienne Nacka, Olga Ousova, Isabelle Rouquette, François Semjen, Frédérique Sgoifo, Thomas Trian
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Children with preschool wheezing represent a very heterogeneous population with wide variability regarding their clinical, inflammatory, obstructive, and/or remodeling patterns. We hypothesized that assessing bronchial remodeling would help clinicians to better characterize severe preschool wheezers. Objectives: The main objective was to identify bronchial remodeling-based latent classes of severe preschool wheezers. Secondary objectives were to compare cross-sectional and longitudinal clinical and biological data between classes and to assess the safety of bronchoscopy. Methods: This double-center prospective study (NCT02806466) included severe preschool wheezers (1-5 yr old) requiring fiberoptic bronchoscopy. Bronchial remodeling parameters (i.e., epithelial integrity, reticular basement membrane [RBM] thickness, mucus gland, fibrosis and bronchial smooth muscle [BSM] areas, the density of blood vessels, and RBM-BSM distance) were assessed and evaluated by latent class analysis. An independent cohort of severe preschool wheezers (NCT04558671) was used to validate our results. Measurements and Main Results: Fiberoptic bronchoscopy procedures were well tolerated. A two-class model was identified: Class BR1 was characterized by increased RBM thickness, normalized BSM area, the density of blood vessels, decreased mucus gland area, fibrosis, and RBM-BSM distance compared with Class BR2. No significant differences were found between classes in the year before fiberoptic bronchoscopy. By contrast, Class BR1 was associated with a shorter time to first exacerbation and an increased risk of both frequent (3 or more) and severe exacerbations during the year after bronchoscopy in the two cohorts. Conclusions: Assessing bronchial remodeling identified severe preschool wheezers at risk of frequent and severe subsequent exacerbations with a favorable benefit to risk ratio.
Beyond borders: cystic fibrosis survival between Australia, Canada, France and New Zealand
Authors: Adèle Coriati, Xiayi Ma, Jenna Sykes, Sanja Stanojevic, Rasa Ruseckaite, Lydie Lemonnier, Clémence Dehillotte, Jan Tate, Catherine Ann Byrnes, Scott C Bell, Pierre Regis Burgel, Anne L Stephenson
Journal: Thorax (2022)

Background Life expectancy for people with cystic fibrosis (CF) varies considerably both within and between countries. The objective of this study was to compare survival among countries with single-payer healthcare systems while accounting for markers of disease severity. Methods This cohort study used data from established national CF registries in Australia, Canada, France and New Zealand from 2015 to 2019. Median age of survival for each of the four countries was estimated using the Kaplan-Meier method. A Cox proportional hazards model was used to compare risk of death between Canada, France and Australia after adjusting for prognostic factors. Due to low number of deaths, New Zealand was not included in final adjusted models. Results Between 2015 and 2019, a total of 14 842 people (3537 Australia, 4434 Canada, 6411 France and 460 New Zealand) were included. The median age of survival was highest in France 65.9 years (95% CI: 59.8 to 76.0) versus 53.3 years (95% CI: 48.9 to 59.8) for Australia, 55.4 years (95% CI: 51.3 to 59.2) for Canada and 54.8 years (95% CI: 40.7 to not available) for New Zealand. After adjusting for individual-level factors, the risk of death was significantly higher in Canada (HR 1.85, 95% CI: 1.48 to 2.32; p&lt;0.001) and Australia (HR 2.08, 95% CI: 1.64 to 2.64; p&lt;0.001) versus France. Interpretation We observed significantly higher survival in France compared with countries with single-payer healthcare systems. The median age of survival in France exceeded 60 years of age despite having the highest proportion of underweight patients which may be due to differences in availability of transplant.
Effect of mutation allele frequency on the risk stratification of myelodysplastic syndrome patients
Authors: Wan‐Hsuan Lee, Chien‐Chin Lin, Cheng‐Hong Tsai, Mei‐Hsuan Tseng, Yuan‐Yeh Kuo, Ming‐Chih Liu, Jih‐Luh Tang, Hsun‐I Sun, Yi‐Kuang Chuang, Wen‐Chien Chou, Hsin‐An Hou, Hwei‐Fang Tien
Journal: American Journal of Hematology (2022)

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal myeloid malignancies. Though several recurrent mutations are closely correlated with clinical outcomes, data concerning the association between mutation variant allele frequencies (VAF) and prognosis are limited. In this study, we performed comprehensive VAF analyses of relevant myeloid-malignancy related mutations in 698 MDS patients and correlated the results with their prognosis. Mutation VAF in DNMT3A, TET2, ASXL1, EZH2, SETBP1, BCOR, SFSF2, ZRSR2, and TP53 mutations correlated with outcomes. In multivariable analysis, DNMT3A and ZRSR2 mutations with high VAF and mutant IDH2, CBL, U2AF1, and TP53 were independent poor prognostic factors for overall survival. A substantial portion of patients in each revised International Prognostic Scoring System (IPSS-R) risk group could be adjusted to different prognostic groups based on the integrated VAF and mutational profiles. Patients with these unfavorable mutations in each IPSS-R risk subgroup had survivals worse than other patients of the same risk but similar to those in the next higher-risk subgroup. Furthermore, patients harboring U2AF1 mutation might benefit from hypomethylating agents. This study demonstrated the critical role of VAF of mutations for risk stratification in MDS patients and may be incorporated in novel scoring systems.
Seroconversion rate and socio-economic and ethnic risk factors for SARS-CoV-2 infection in children in a population-based cohort, Germany, June 2020 to February 2021
Authors: Folke Brinkmann, Hans H Diebner, Chantal Matenar, Anne Schlegtendal, Lynn Eitner, Nina Timmesfeld, Christoph Maier, Thomas Lücke
Journal: Eurosurveillance (2022)

Introduction Socio-economic and ethnic background have been discussed as possible risk factors for SARS-CoV-2 infections in children. Improved knowledge could lead to tailored prevention strategies and help improve infection control. Aim We aimed to identify risk factors for SARS-CoV-2 infections in children in the first and second wave of the pandemic. Methods We performed an observational population-based cohort study in children (6 months–18 years) scheduled for legally required preventive examination and their parents in a metropolitan region in Germany. Primary endpoint was the SARS-CoV-2 seroconversion rate during the study period. Risk factors assessed included age, pre-existing medical conditions, socio-economic factors and ethnicity. Results We included 2,124 children and their parents. Seroconversion rates among children in all age groups increased 3–4-fold from June 2020 to February 2021. Only 24 of 58 (41%) seropositive children reported symptoms. In 51% of infected children, at least one parent was also SARS-CoV-2-positive. Low level of parental education (OR = 3.13; 95% CI: 0.72–13.69) non-significantly increased the risk of infection. Of the total cohort, 38.5% had a migration background, 9% of Turkish and 5% of Middle Eastern origin, and had the highest risk for SARS-CoV-2 infections (OR = 6.24; 95% CI: 1.38–28.12 and OR = 6.44 (95% CI: 1.14–36.45) after adjustment for other risk factors. Conclusion In the second half of 2020, seroprevalence for SARS-CoV-2 in children increased especially in families with lower-socioeconomic status. Culture-sensitive approaches are essential to limit transmission and could serve as a blueprint for vaccination strategies.
Type II collagen facilitates gouty arthritis by regulating MSU crystallisation and inflammatory cell recruitment
Authors: HanLin Xu, Bohan Zhang, Yaxin Chen, Fengzhen Zeng, Wenjuan Wang, Ziyi Chen, Ling Cao, Jun Shi, Jun Chen, Xiaoxia Zhu, Yu Xue, Rui He, MinBiao Ji, YingHui Hua
Journal: Annals of the Rheumatic Diseases (2022)

Objective Increasing evidence suggests that impaired cartilage is a substantial risk factor for the progression from hyperuricaemia to gout. Since the relationship between cartilage matrix protein and gout flares remains unclear, we investigated its role in monosodium urate (MSU) crystallisation and following inflammation. Methods Briefly, we screened for cartilage matrix in synovial fluid from gouty arthritis patients with cartilage injuries. After identifying a correlation between crystals and matrix molecules, we conducted image analysis and classification of crystal phenotypes according to their morphology. We then evaluated the differences between the cartilage matrix protein-MSU complex and the pure MSU crystal in their interaction with immune cells and identified the related signalling pathway. Results Type II collagen (CII) was found to be enriched around MSU crystals in synovial fluid after cartilage injury. Imaging analysis revealed that CII regulated the morphology of single crystals and the alignment of crystal bows in the co-crystalline system, leading to greater phagocytosis and oxidative stress in macrophages. Furthermore, CII upregulated MSU-induced chemokine and proinflammatory cytokine expression in macrophages, thereby promoting the recruitment of leucocytes. Mechanistically, CII enhanced MSU-mediated inflammation by activating the integrin β1(ITGB1)-dependent TLR2/4-NF-κB signal pathway. Conclusion Our study demonstrates that the release of CII and protein-crystal adsorption modifies the crystal profile and promotes the early immune response in MSU-mediated inflammation. These findings open up a new path for understanding the relationship between cartilage injuries and the early immune response in gout flares.
Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB–IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): an interim analysis of a randomised, triple-blind, phase 3 trial
Authors: Mary O'Brien, Luis Paz-Ares, Sandrine Marreaud, Urania Dafni, Kersti Oselin, Libor Havel, Emilio Esteban, Dolores Isla, Alex Martinez-Marti, Martin Faehling, Masahiro Tsuboi, Jong-Seok Lee, Kazuhiko Nakagawa, Jing Yang, Ayman Samkari, Steven M Keller, Murielle Mauer, Nitish Jha, Rolf Stahel, Benjamin Besse, Solange Peters
Journal: The Lancet Oncology (2022)
Treatment of Cryptococcal Meningitis: How Have We Got Here and Where are We Going?
Authors: Nguyen Thi Thuy Ngan, Barnaby Flower, Jeremy N. Day
Journal: Drugs (2022)

Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by adulthood, but symptomatic infection only occurs in a minority, in most cases, months or years after exposure. Disease has been described in almost all tissues, but it is the organism's tropism for the central nervous system that results in the most devastating illness. While invasive disease can occur in the immunocompetent, the greatest burden by far is in immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV), organ transplant recipients and those on glucocorticoid therapy or other immunosuppressive drugs. Clinical presentation is variable, but diagnosis is usually straightforward, with cerebrospinal fluid microscopy, culture, and antigen testing proving significantly more sensitive than diagnostic tests for other brain infections. Although disease incidence has reduced since the advent of effective HIV therapy, mortality when disease occurs remains extremely high, and has changed little in recent decades. This Therapy in Practice review is an update of a talk first given by JND at the European Congress on Clinical Microbiology and Infectious Diseases in 2019 in the Netherlands. The review contextualizes the most recently published World Health Organization (WHO) guidelines for the treatment of HIV-associated cryptococcal meningitis in terms of the data from large, randomized, controlled trials published between 1997 and 2022. We discuss the rationale for induction and maintenance therapy and the efficacy and undesirable effects of the current therapeutic armamentarium of amphotericin, flucytosine and fluconazole. We address recent research into repurposed drugs such as sertraline and tamoxifen, and potential future treatment options, including the novel antifungals fosmanogepix, efungumab and oteseconazole, and non-pharmaceutical solutions such as neurapheresis cerebrospinal fluid filtration.
Hydroxychloroquine Dose per Ophthalmology Guidelines and the Risk of Systemic Lupus Erythematosus Flares
Authors: April M. Jorge, Christian Mancini, Baijun Zhou, Gary Ho, Yuqing Zhang, Karen Costenbader, Hyon K. Choi
Journal: JAMA (2022)

This study of an academic medical center patient cohort with systemic lupus erythematosus (SLE) investigates the association between hydroxychloroquine dose based on current guidelines and risk of lupus flares.
Short-term supplementation with ω-3 polyunsaturated fatty acids modulates primarily mucolytic species from the gut luminal mucin niche in a human fermentation system
Authors: Charlène Roussel, Sara Anunciação Braga Guebara, Pier-Luc Plante, Yves Desjardins, Vincenzo Di Marzo, Cristoforo Silvestri
Journal: Gut Microbes (2022)

Consumption of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) provides multifaceted health benefits. Recent studies suggest that ω-3 PUFAs modulate the gut microbiota by enhancing health-promoting bacteria, such as the mucin specialist Akkermansia muciniphila. However, these prebiotic properties have been poorly investigated and direct effects on the gut microbiome have never been explored dynamically across gut regions and niches (lumen vs. mucus-associated microbiota). Thus, we studied the effects of 1 week EPA- and DHA-enriched ω-3 fish-oil supplementation on the composition and functionality of the human microbiome in a Mucosal Simulator of the Human Intestinal Microbial Ecosystem (M-SHIME®). Gut microbial communities derived from one individual harvested in two different seasons were tested in duplicate. Luminal and outer mucus-associated microbiota of the ileum, ascending, transverse and descending colons were cultivated over 28 d from fecal inoculates and supplemented with ω-3 PUFAs for the last 7 d. We show that ω-3 PUFA supplementation modulates the microbiota in a gut region- and niche-dependent fashion. The outer mucus-associated microbiota displayed a higher resilience than the luminal mucin habitat to ω-3 PUFAs, with a remarkable blooming of Akkermansia muciniphila in opposition to a decrease of Firmicutes-mucolytic bacteria. The ω-3 PUFAs also induced a gradual and significant depletion of non-mucolytic Clostridia members in luminal habitats. Finally, increased concentrations of the short chain fatty acids (SCFA) propionate in colon regions at the end of the supplementation was associated positively with the bloom of Akkermansia muciniphila and members of the Desulfovibrionia class.
Evaluation of Systemwide Improvement Programs to Optimize Time to Surgery for Patients With Hip Fractures
Authors: Pariswi Tewari, Brian F. Sweeney, Jacie L. Lemos, Lauren Shapiro, Michael J. Gardner, Arden M. Morris, Laurence C. Baker, Alex S. Harris, Robin N. Kamal
Journal: JAMA Network Open (2022)

Importance Longer time to surgery (TTS) for hip fractures has been associated with higher rates of postoperative complications and mortality. Given that more than 300 000 adults are hospitalized for hip fractures in the United States each year, various improvement programs have been implemented to reduce TTS with variable results, attributed to contextual patient- and system-level factors. Objective To catalog TTS improvement programs, identify their results, and categorize program strategies according to Expert Recommendations for Implementing Change (ERIC), highlighting components of successful improvement programs within their associated contexts and seeking to guide health care systems in implementing programs designed to reduce TTS. Evidence Review A systematic review was conducted per the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Three databases (MEDLINE/PubMed, EMBASE, and Cochrane Trials) were searched for studies published between 2000 and 2021 that reported on improvement programs for hip fracture TTS. Observational studies in high-income country settings, including patients with surgical, low-impact, nonpathological hip fractures aged 50 years or older, were considered for review. Improvement programs were assessed for their association with decreased TTS, and ERIC strategies were matched to improvement program components. Findings Preliminary literature searches yielded 1683 articles, of which 69 articles were included for final analysis. Among the 69 improvement programs, 49 were associated with significantly decreased TTS, and 20 programs did not report significant decreases in TTS. Among 49 successful improvement programs, the 5 most common ERIC strategies were (1) assess for readiness and identify barriers and facilitators, (2) develop a formal implementation blueprint, (3) identify and prepare champions, (4) promote network weaving, and (5) develop resource-sharing agreements. Conclusions and Relevance In this systematic review, certain components (eg, identifying barriers and facilitators to program implementation, developing a formal implementation blueprint, preparing intervention champions) are common among improvement programs that were associated with reducing TTS and may inform the approach of hospital systems developing similar programs. Other strategies had mixed results, suggesting local contextual factors (eg, operating room availability) may affect their success. To contextualize the success of a given improvement program across different clinical settings, subsequent investigation must elucidate the association between interventional success and facility-level factors influencing TTS, such as hospital census and type, teaching status, annual surgical volume, and other factors.
Skin biomarkers predict development of atopic dermatitis in infancy
Authors: Maria Rasmussen Rinnov, Anne‐Sofie Halling, Trine Gerner, Nina Haarup Ravn, Mette Hjorslev Knudgaard, Simon Trautner, Susan M. I. Goorden, Karen J. M. Ghauharali‐van der Vlugt, Femke S. Stet, Lone Skov, Simon Francis Thomsen, Alexander Egeberg, Aske L. L. Rosted, Troels Petersen, Ivone Jakasa, Christoph Riethmüller, Sanja Kezic, Jacob P. Thyssen
Journal: Allergy (2022)

There is currently no insight into biomarkers that can predict the onset of pediatric atopic dermatitis (AD).Nested in a prospective birth cohort study that examined the occurrence of physician-diagnosed AD in 300 children, 44 random children with onset of AD in the first year of life were matched on sex and season of birth with 44 children who did not develop AD. Natural moisturizing factor (NMF), corneocyte surface protrusions, cytokines, free sphingoid bases (SBs) of different chain lengths and their ceramides were analyzed from tape strips collected at 2 months of age before onset of AD using liquid chromatography, atomic force microscopy, multiplex immunoassay, and liquid chromatography mass spectrometry, respectively.Significant alterations were observed for four lipid markers, with phytosphingosine ([P]) levels being significantly lower in children who developed AD compared with children who did not (median 240 pmol/mg vs. 540 pmol/mg, p < 0.001). The two groups of children differed in the relative amounts of SB of different chain lengths (C17, C18 and C20). Thymus- and activation-regulated chemokine (TARC/CCL17) was slightly higher in children who developed AD, whereas NMF and corneocyte surface texture were similar. AD severity assessed by the eczema area and severity index (EASI) at disease onset was 4.2 (2.0;7.2). [P] had the highest prediction accuracy among the biomarkers (75.6%), whereas the combination of 5 lipid ratios gave an accuracy of 89.4%.This study showed that levels and SB chain length were altered in infants who later developed AD, and that TARC/CCL17 levels were higher.